Prostate cancer is the leading cause of cancer-related deaths in North America and Europe. Localized prostate tumours are commonly diagnosed and conventionally treated by radical prostatectomy. After an initially effective hormone therapy, the advanced disease led to the development of hormone-refractory, drug-resistant malignancy. To date, there is still no cure available for patients with advanced disease.
Cell cultures established directly from patient tumors are powerful research resource for studying cancer cell biology and for the development of new strategies against cancer. Some cellular or xenografted models have been established from different tissue origins but most of these models have been obtained from prostate tumor metastases or have been artificially established.
Over the years a number of new cell lines and clonal derivatives of these original lines have been developed by investigators using a variety of methods. Although there is a real need of identifying cells at the origin of prostate cancer, there are still few culture models to study the early step of the oncogenesis of prostate cancer. Therefore it is still a challenge to obtain new cancer models that may better reflect the mechanisms of local tumor progression and to identify cells at the origin of prostate cancer, potentially including cancer stem cells.
Human prostate cells are known to be one of the most difficult cell types to develop into continuously growing culture and considerable research efforts have been directed toward the establishment of new prostate cancer models from the primary tumours.
In view of the difficulties to obtain human prostate cancer cell lines, several teams developed immortalization approaches of prostate tissues, often benign ones. Thereby, several epithelial cell lines were obtained by immortalization with SV40 large T-antigen. However, the major impact of SV40 large T-antigen, a potent oncogene, in their preparation makes these cell lines a very artificial model of prostate cancer. Alternatively, human telomerase catalytic subunit (hTERT) has been successfully used to immortalize human prostate epithelial (HPE) cells from normal prostate or primary tumors, named HPET cells. Several groups had chosen this strategy and established immortalized cultures which are to date the most representative of the authentic prostate cancer cells (Yasunaga et al., 2001; Gu et al., 2004; Litvinov et al., 2006; Daly-Burns et al. 2007; Gu et al., 2007; Miki et al., 2007).
Yet, only two continuously cultured human primary epithelial prostate cancer cell lines have been obtained, the E006AA cell lines (Koochekpour et al., 2004) and the HH870 (Selvan et al., 2005), with very few available published results. Three other cell lines established from a primary tumor are only maintained in xenograft (van Bokhoven et al., 2003). A third human prostate cancer model was recently established in vitro from a trans-rectal prostate needle biopsy specimen but it was unable to grow in nude mice (Attard et al., 2009). Currently, prostate cancer models, directly derived from primary tumors, enabling both in vivo and in vitro approaches and representing the early stages of this cancer are still lacking.
Since 2004, docetaxel (Taxotere®) is become the reference treatment of hormone-resistant metastatic prostate cancer. However, despite the survival benefit of this drug, a high number of patients treated with docetaxel develop a chemotherapy resistance. This is why cellular models of prostate cancer resistant to docetaxel are so interesting and useful.
In order to study the resistance to drugs, several teams obtained prostate cancer models resistant to different drugs. DU145 and PC3 cells resistant to docetaxel or paclitaxel (Makarovskiy et al., 2002; Patterson et al., 2006; Takeda et al, 2007) and LNCaP cells resistant to cisplatin (Nomura et al., 2005) were obtained and are used by several groups in different studies (Kucukzeybek et al., 2008; Erten et al., 2009; Lo Nigro et al., 2008; Sowery et al., 2008; Sallman et al., 2007).
The use of cellular models is useful to eliminate the cytotoxic compounds in the early and later stages of drug discovery that can help reduce the costs of research and development. In prostate cancer, the investigators are now focused on how to enhance the cytostatic and cytotoxic effects of docetaxel by combining it with novel anticancer agents for the treatment of prostate cancer. The use of docetaxel-resistant and the corresponding parental prostate cancer cell lines is thus an indispensable tool to assess new drug efficacy.
Furthermore, the search for correlations between gene expression profiles and chemosensitivity has been initiated on in vitro models in large screening projects. The best example is the set of 60 human tumor cell lines of the US National Cancer Institute (NCI) designed for the screening of 3,000 compounds per year for potential anticancer activity (Shoemaker, 2006). This strategy may certainly allow for progress in the identification of individual patients who may benefit from a specific chemotherapy.
Moreover the availability of drug-resistant cellular models with tumorigenic properties offers the possibility to establish animal models useful for both biomarkers identification and screening of potential therapeutic agents.
Consequently, a prostate cancer cell line, either sensitive or resistant to a cytotoxic drug, is of great interest for pharmaceutical companies.